Summary
In hepatitis B virus (HBV) monoinfection, alanine aminotransferase (ALT) levels are linearly correlated with HBV DNA levels and lamivudine resistance. In human immunodeficiency virus (HIV)/HBV co-infection, little is known about the association between ALT, HBV DNA, and lamivudine resistance. We assessed HBV DNA, lamivudine resistance and ALT levels in 45 time points in 11 patients with HIV/HBV co-infection during lamivudine-containing antiretroviral therapy. High HBV DNA levels (>106 copies/mL) and lamivudine resistance developed in 45% and 91% of patients, respectively. However, ALT levels were not elevated in the setting of high HBV DNA levels (mean ALT, 48 IU/mL) or lamivudine resistance (mean ALT, 44 IU/mL). HBV viraemia and lamivudine resistance during extended lamivudine-containing antiretroviral therapy are common in HIV/HBV co-infection, occurring in the absence of significant ALT elevations. In HIV/HBV co-infection, measurement of HBV DNA and HBV resistance mutations may identify HBV virological failure before biochemical changes and should be routinely used in the management of HIV/HBV co-infection.
Keywords: HIV infection, highly active antiretroviral therapy, hepatitis B infection, hepatitis B drug resistance, lamivudine
INTRODUCTION
Upto 10% of human immunodeficiency virus (HIV)-infected individuals1 are co-infected with hepatitis B virus (HBV). In resource-limited settings, many HIV/HBV co-infected individuals will receive lamivudine-containing highly active antiretroviral therapy (HAART), resulting in lamivudine monotherapy for hepatitis B infection. Alanine aminotransferase (ALT) values are markers of hepatic inflammation and used as tools in the management of HBV infection. In HBV monoinfection, there is a linear correlation between serum HBV DNA and ALT levels.2 During lamivudine resistance, hepatitis flares are common; in those with transaminitis at five years of therapy, lamivudine resistance was temporarily associated with hepatic flare in >80% of individuals.3 In HIV/HBV co-infection, both HBV viraemia4 and lamivudine resistance5 are more frequent but little is known about the association between HBV viraemia, lamivudine resistance and ALT levels. In order to study the effects of lamivudine monotherapy for HBV infection in the setting of HAART, we sought to characterize HBV viraemia, lamivudine resistance and serum ALT levels in HIV/HBV co-infected individuals receiving extended lamivudine-containing therapy, in the era before the availability of other anti-HBV active nucleos(t)ide therapy.
METHODS
We evaluated 45 annual serum samples from 11 HIV/HBV co-infected patients who received lamivudine-containing antiretroviral therapy from 1996 to 2004. The mean duration of lamivudine therapy at study entry and termination was 2.4 and 5.6 years, respectively. All were males; 4/11 (36%) were non-white and 5/11 (45%) had hepatitis C virus co-infection. The study was approved by the San Mateo County Medical Center institutional review board.
Serum HBV DNA was determined using a real-time polymerase chain reaction (lower limit of detection 102 copies/mL).6 HBV lamivudine resistance and genotype were identified by INNO-LiPA HBV DR and Genotyping, (Innogenetics). Rebound viraemia was defined as stable then rebounding HBV DNA or persistently elevated HBV DNA levels. An HBV viral load (VL) ≥106 copies/mL was defined as a high HBV DNA levels.
RESULTS
At study entry, median HIV VLs and CD4 counts were 3.3 log10 copies/mL and 202 cells/µL, respectively. Ten of 11 patients were infected with HBV genotype A and one with genotype D (Table 1).
Table 1.
Patient, virological and clinical characteristics
| Patient | Age* | HCV† | Genotype | YMDD‡ | Lamivudine duration§ |
|---|---|---|---|---|---|
| 1 | 43 | Yes | A | Yes | 8 |
| 2 | 48 | No | A | Yes | 7 |
| 3 | 41 | Yes | A | Yes | 6 |
| 4 | 43 | No | A | Yes | 6 |
| 5 | 31 | Yes | A | Yes | 7 |
| 6 | 51 | Yes | A | Yes | 2 |
| 7 | 35 | No | A | Yes | 6 |
| 8 | 44 | No | A | Yes | 4 |
| 9 | 37 | No | A | Yes | 4 |
| 10 | 50 | Yes | D | No | 7 |
| 11 | 38 | No | A | Yes | 5 |
Age at study entry
HCV = hepatitis C antibody positive
YMDD: lamivudine resistance
Lamivudine duration at study end
After a mean of 5.6 years of lamivudine-containing antiretroviral therapy, 91% (10/11) individuals and 76% (34/45) of samples had detectable HBV DNA (>200 copies/mL). In these patients, 64% (7/11) had rebound HBV viraemia, which was associated with lower mean CD4 counts (174 versus 379 cells/µL; P, < 0.08) and higher mean HIV VLs (4.8 log10 copies/mL versus 2.9 log10 copies/mL, P, < 0.03) at study entry. Rebound HBV viraemia usually occurred after more than four years of lamivudine-containing antiretroviral therapy. Lamivudine resistance was present in 10/11 (91%).
Serum HBV DNA and ALT levels were measured in all patients and in 40/45 samples. Five patients (10 isolates) had HBV VLs ≥ 106 copies/mL. Mean ALT values were not different between those with and without HBV VL ≥ 106 copies/mL, i.e. 48 and 42 IU/L, respectively (P = 0.65). Only 4/10 (40%) of samples with HBV VL ≥ 106 copies/mL had an ALT >51 IU/mL and none of the serum ALT determinations were > 125 IU/mL Mean HBV DNA levels during lamivudine resistance were higher (4.5 log10 versus 3.2 log10, respectively; P, < 0.07), but there was no difference between ALT levels in wild-type HBV viraemia compared with lamivudine-resistant HBV viraemia, 43 versus 44 IU/mL, respectively (P = 0.96). Although ALT levels were slightly higher during lamivudine resistance associated with HBV VL ≥ 106 copies/mL (52 versus 37 IU/mL), this difference did not reach statistical significance.
DISCUSSION
As lamivudine resistance is temporarily associated with transaminitis, recommendations for monitoring lamivudine resistance in HIV/HBV co-infection management also include the assessment of aminotransferase levels. However, our observations demonstrate that HIV/HBV co-infected patients do not demonstrate significant ALT elevations with high HBV DNA levels or the emergence of lamivudine resistance, limiting the utility of ALT as a surrogate marker for HBV DNA levels and resistance in this population. A limitation of this study was its small sample size. However, even in larger cohorts of HIV/HBV co-infected patients with lamivudine resistance only mild ALT elevations (<2.5 × ULN)7,8 have been reported and usually with HBV VLs of > 108 copies/mL. These milder ALT elevations are in contrast to the higher ALT elevations seen in HBV monoinfection; in a large study of lamivudine resistance all ALT flares with lamivudine resistance occurred at elevations of 3 × ULN.
In HBV infection, CD4 cells are responsible for recognizing viral antigen and secreting cytokines.9 In HIV/HBV co-infection, CD4 depletion may abrogate this response. Paradoxically, despite higher levels of HBV DNA and lower ALT values,10 progression to cirrhosis occurs at a higher rate, reinforcing the need to identify the appropriate markers of disease progression.
In HIV/HBV co-infection, including those in resource-limited settings, HBV DNA levels and HBV resistance testing should be considered in the routine monitoring of HIV/HBV co-infection and the failure of antiviral therapy, as ALT levels may not reliably indicate HBV replication or the emergence of HBV lamivudine resistance.
ACKNOWLEDGMENTS
This work was supported by NIH grant T32 AI052073 and a Bristol Myers Squibb Fellowship Award (DB). The authors would also like to acknowledge Innogenetics for supplying the INNO-LiPA HBV DR and Genotyping kits.
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